Here are a few key points regarding carfilzomib-associated cardiac adverse events based on clinical trial data: - CHF and hypertension are the most common cardiac AEs seen with carfilzomib. Rates are generally higher than with bortezomib or lenalidomide doublets. - Hypertension can usually be managed medically with antihypertensives like ACE inhibitors. Close monitoring of BP is important. - Risk factors for cardiac AEs include older age, prior cardiac history, diabetes, renal dysfunction. However, events can still occur in lower risk patients. - No definitive biomarkers yet to reliably predict risk. Troponin elevation during treatment may indicate higher risk but

1. RELAPSED REFRACTORY MULTIPLE MYELOMA
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE &
SPECIALITY HOSPITALS

2. MULTIPLE MYELOMA – DISEASE TRAJECTORY
MM is a Marathon, Not a Sprint

3. Drach J.ASH 2012.; Morgan GI, et al.Nat Rev Cancer.
2012;12:335‐348.
MULTIPLE MYELOMA
…Not Just One Disease!
©
3
I

4. Multiple Myeloma: Current scenario
Leukemia.2018;32:252-262
• Despite all the advances including Proteasome Inhibitors (Pis), Immunomodulators (IMiDs) &
Monoclonal Antibodies (MAbs), treatment of MM remains challenging
• Relapses & disease progression are common even after CR & MRD negativity
• RRMM acquires additional mutations rendering the disease more resistant
• With disease progression, remission duration becomes shorter & shorter

5. MYELOMA CLONAL EVOLUTION TO
HIGH RISK
…thehigh-risk biological states of multiple myeloma are the end stage of a
multi-step progression system characteristic of the disease…
Pawlyn C and Morgan GJ Nature Reviews

6. Pawlyn C and Morgan GJ Nature Reviews
Cancer 2017

7. RELAPSED AND REFRACTORY
MM: OS
1. Kumar SK, et al. Leukemia 2012
2. Usmani S, et al. Presented at ASH 2015; abstract

8. Primary Refractory myeloma.
It is a disease that is non responsive in patients who have never
achieved a minor response with any therapy
Relapsed myeloma.
After a period of being off therapy, it requires the initiation of salvage therapy
Relapsed and refractory myeloma.
It is non responsive while being on salvage therapy (achieved minor response or better at some point in their
disease course) or progress within 60 days of last therapy
DEFINITIONS OF
RELAPSED/REFRACTORY MM

9. Indications of treatment at relapse
Sonneveld P et al.Haematologica.2016;101(4):396-406

10. Extramedullary
disease PCL, High
LDH
Adverse
cytogenetic
abnormalities
ISS stage II/III at
Timing
of
relapse
Speed of M
protein rise
CRAB
criteria
Other
factor
s
Sharp rise (doubling time
< 2 months)
Rapid onset
Hypercalcemia
Severe anemia
Acute renal
failure
Skeletal-related events
Aggressive Non
Aggressive
Short duration of
response or
progression while on
therapy
Long duration of
response
Gradual rise over
several months
Slow onset
Minimal complication
No
extramedullary
disease
LDH in normal range
No
PCL
NOT ALL RELAPSES IN MM ARE
THE SAME
Adapted from Sonneveld P Hematology

11. TUMOR CELL
RELATED
-Ploidy (hyperdiploidy
vs hypodiploidy)
- Translocation
t(4;14)
t(6;14)
t(11;14)
t(14;16)
t(14;20)
- Monosomy 13 (by
citogenetics)
- 17p deletion (or loss of TP53)
- 1q amplification
- 1p-
- Complex karyotypes
- Lactate dehydrogenase
(above
normal)
-Circulating plasma cells
(any number)
-Plasma cell growth rate
(>3% by flow cytometry)
- Gene expression profile
TUMOR BURDEN
- Durie-Salmon stage
- International Staging System
- Extramedullary disease
PATIENT RELATED
- Age
- Performance status
- Renal failure
- Frailty (IMWG guidelines)
PROGNOSTIC FACTORS IN
RELAPSED MM
Dingli D et al Mayo Clin Proc

12. SMART RISK CLASSIFICATION IN
RELAPSED MM
MSMART: Mayo Stratification for Myeloma and Risk-Adapted Therapy.
Dingli D et al Mayo Clin Proc 2017
HIGH RISK
• Primary refractory
disease
• Relapse < 12
months from
ASCT
• Progression within
the first year of
diagnosis
• FISH
- Deletion 17p
- t(14;16)
- t(14;20)
• High risk GEP
INTERMEDIATE
RISK
• FISH
- t(4;14)
- 1q amp
• High “S” phase
STANDARD RISK
All others including
- Trisomies
- t(11;14)
- t(6;14)

13. Bianchi G, et al. Blood.
2015;126:300‐310.
MULTIMODALITY TARGETING OF MM IN THE CONTEXT OF
, THE BM MICROENVIRONMENT
1
3

14. Expanding treatment options: mibs-mids-mAbs

15. Case 1
• A 60-year-old male was diagnosed with symptomatic myeloma
• FISH analysis revealed the presence of t(4;14).
• The patient received 4 cycles of VCD with the achievement of a VGPR, followed by melphalan 200mg/m2 and ASCT.
• No consolidation; on lenalidomide maintenance 15mg OD
• Within one year the patient presented with disease progression with anemia and bone pain.
• Renal function and performance status were good at the time of relapse.
Blood. 2017;130(13):1507-1513)

16. Case 1
• What will be your next step in management?
• Doublet or Triplet?
• Which regimen?
• Re-challenge or switch to another therapy?

17. Case 1
• The patient was treated with the triplet combination KRd
• He responded quickly and achieved a VGPR after the first 2 cycles and CR at cycle 6.
• Last known status -Regimen continued till cycle 15 with a sustained CR, without the
occurrence of significant toxicity
Blood. 2017;130(13):1507-1513)

18. Refractory to Lenalidomide
DVd, DPd,
Isa-Pd
Alternatives including if
Dara Refractory:
KPd or Dara-KPd, EPd, DKd
Frail: Ixa-Pd, Pd, PCd
First Relapse*
Not Refractory to Lenalidomide¶
DRd
Alternatives including if
Dara Refractory:
KRd or Ixa-Rd
Or ERd, Kd-Dara / Kd-Isa
*Consider salvage auto transplant in eligible patients
¶Relapse occurring while off all therapy, or while on small doses of single-agent lenalidomide, or
on bortezomib maintenance
Myeloma: First Relapse
Rajkumar SV © 2020
P. Moreau
Kd-dara, Kd-Isa
Pom-Vd,

19. 1st Relapse After Bortezomib-Based Induction (Len Naive or Exposed but Not Refractory)
Lenalidomide-Based Regimens: Efficacy (Rd vs triplets with Rd backbone)
RD
Triplets
(with Rd as backbone)
DaraRd, KRd,
IRd, or ERd
First relapse
after bortezomib-based induction
This table is provided for ease of viewing information from multiple trials with different patient populations. Direct
comparison across trials is not intended and should not be inferred.
1. Bahlis. Leukemia. 2020;34:1875. 2. Seigel. JCO. 2018;36:728. 3. Dimopoulos. Blood Cancer J. 2020;10:91. 4. Moreau. NEJM. 2016;374:1621.
Efficacy
POLLUX[1]
(N = 569)
DaraRd vs Rd
ASPIRE[2]
(N = 792)
KRd vs Rd
ELOQUENT-2[3]
(N = 646)
ERd vs Rd
TOURMALINE-MM1[4]
(N = 722)
IRd vs Rd
PFS HR (▲m)
0.44 (▲ 27 mos)
44.5 mos vs 17.5 mos
0.66 (▲ 9.5 mos)
26.1 mos vs 16.6 mos
0.72 (▲ 4.5 mos)
19.4 mos vs 14.9 mos
0.74 (▲ 5.9 mos)
20.6 mos vs. 14.7 mos
Economical constrains: RD + Cyclophosphamide , VTD ( if TFI > 12 mos)

20. ASPIRE: Carfilzomib, Revlimid and Dexamethasone (KRd) vs Revlimid and
Dexamethasone (Rd) in RRMM

21. ASPIRE: PFS BY CYTOGENETIC RISK STATUS
AT BASELINE

22. POLLUX: Daratumumab, Revlimid and Dexamethasone (DRd) vs Revlimid an
Dexamethasone (Rd) in RRMM

23. Standard risk: HR 0.41 median PFS NR
vs 19.9
High risk: HR 0.54 median PFS 26.8 vs
8.8
POLLUX: PFS UPDATE BY CYTOGENETIC RISK STATUS (NGS AND FISH
KARYOTIPING COMBINED)

24. ELOQUENT-2: ELOTUZUMAB, Revlimid and Dexamethasone (ERd) vs Rev
Dexamethasone (Rd) in RRMM

25. ELOQUENT-2: PFS BY CYTOGENETIC RISK STATUS
AT BASELINE
Dimopoulos MA et al Cancer
Standard Risk
Figure S1. Kaplan–Meier curves of PFS for (a) high-risk and (b) standard-risk patients
according to IMWG risk definition. High risk was defined as ISS stage II or III and t(4;14) or
del(17p) abnormality; low risk as ISS stage I or II and the absence of t(4;14), del(17p) and 1q21
abnormalities, and age <55 years; and standard risk as not meeting either the definition of high
or low risk.
High Risk

26. TOURMALINE-MM1: Ixazomib, Revlimid and Dexamethasone (IRd) vs Revli
Dexamethasone (Rd) in RRMM
including primary refractory
patients

27. TOURMALINE-MM1: PFS BY CYTOGENETIC RISK STATUS
AT BASELINE
Avet-Loiseau H, et al. Blood

28. Novel agent +Rd combinations in RRMM patients
• In terms of efficacy, cross-trial comparisons are difficult because of substantial
differences in patient populations. However, an evaluation of hazard ratios (HRs)
is a reliable method to assess PFS data and can be used to compare different trials

29. Novel agent +Rd combinations in RRMM patients
• The use of triplet combinations in relapse is particularly important for patients with
adverse cytogenetics.
• This Patient has t(4;14), and the HR for this specific subgroup of patients is also in favor
of the recently approved triplet combinations vs Rd and ranges from
- 0.44 (POLLUX trial) to 0.70 (ASPIRE trial)
- 0.52 in the ELOQUENT 2 trial and
- 0.64 in the TOURMALINE 1 trial

30. 1st Relapse Following Continuous Lenalidomide/Dex, Len Maintenance, VRD-Rd ... will be considered Len-Refrac
Proteasome Inhibitors-Based Regimens: Efficacy
1. Dimopoulos. Lancet Oncol. 2016;17:P27. 2. Moreau. Leukemia. 2017;31:115. 3. Mateos. ASH 2020. Abstr 415.
4. Spencer. Haematologica. 2018;103:2079. 5. Dimopoulos. Lancet. 2020;396:186. 6. Moreau. EHA 2020. Abstr
LB2603.. 7. San-Miguel. Lancet Oncol. 2014;15:1195. 8. Reece. JCO. 2008;26:4777.
Doublets
Kd or Vd
First relapse
after IMiD-based induction
Triplets based on PI
DaraVD, PomVD
Or Dara-KD
Efficacy
ENDEAVOR
(N = 929)
Kd vs Vd1,2
KCyDex
(N = 198)
KCd vs Kd3
CASTOR
(N = 498)
DaraVd vs Vd4
CANDOR
(N = 466)
DKd vs Kd5
IKEMA
(N = 302)
IKd vs Kd6
PFS HR
(▲mos)
0.53 (▲ 9)
18.7 vs 9.4 mos
1 (▲ 5)
20.7 vs 15.2 mos
0.31 (▲ 9)
16.7 vs 7.1 mos
0.63 (▲ NE)
NE vs 15.8 mos
0.53 (▲NE)
NE vs 19.2 mos
Len Refract,
experimental
arm, % (mPFS)
24% (8.6 mos) 36% (26 mos) 18% (9.3 mos) 31.7% (NA) 32% (NA)
Economical Constrains. VMP/VCD (16 m; 83% at 1 Yr)8
**PANORAMA-1 PanoVD vs VD (n=768)7: mPFS 12 mos vs 8 mos (HR: 0.63 (▲ 4 m) ; 27.6% CR rate; Only 19% Lena Refractory

31. CASTOR: Daratumumab, Velcade and Dexamethasone (DVd) vs Velcade
Dexamethasone (Vd) in RRMM

32. CASTOR: PFS UPDATE BY CYTOGENETIC
RISK STATUS
Standard risk: HR 0.28 median PFS 18.4
vs 6.8
High risk: HR 0.40 median PFS 13.4 vs
7.2

33. ENDEAVOR: Carfilzomib and Dexamethasone (Kd) vs Bortezomib and
Dexamethasone (Vd) in RRMM

34. High risk Standard risk
Kd Vd Kd Vd
(n=97) (n=113) (n=284) (n=291)
PFS, median
months
(95% CI)
8.8
(6.9–11.3)
6.0
(4.9–8.1)
PFS, median
months
(95% CI)
NE
(18.7–NE)
10.2
(9.3–12.2)
HR (95% CI)
0.646
HR (95% CI)
0.439
(0.453–0.921) (0.333–0.578)
0 6 12 18
Months since randomization
24
KRd
Vd
Proportion
surviving
without
progression
0 12 18 24
Months since randomization
6
KRd
Vd
1.0
Proportion
surviving
without
progression
30
NE, not estimable
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Chang WJ, et al. Leukemia
ENDEAVOR: PFS BY CYTOGENETIC RISK STATUS
AT BASELINE

35. Transplantation After Relapse: PFS
1. Kumar S, et al. Cancer. 2012;118:1585-1592. 2. Cook G, et al. Lancet Oncol. 2014;15:874-885.

36. Carfilzomib associated cardiac adverse events
• What is your experience?
• How to manage hypertension?
• Any markers to predict cardiovascular AEs ?

37. Incidence of cardiac events from phase 3 studies
Cardiac event ASPIRE [ KRd Vs Rd] ENDEAVOR [ Kd Vs Vd ]
CHF all grades 6% vs 4% 8% vs 3%
CHF Gr ≥ 3 4% vs 2% 4.8% Vs 1.8%
Hypertension all grades 15.8% Vs 8.2% 25.9% Vs 9.6%
HTN Gr ≥ 3 5.6% Vs 2.1% 9.5% Vs 2.6%
The association between
carfilzomib dose and cardiac AE incidence is inconclusive
HTN Grades: G1 -pre-HTN: 120–139/80–89 mm Hg, G2: Stage 1 HTN: 140–159/90–99 mmHg or to >140/90 mmHg if
previously in normal range or symptomatic increase in diastolic BP > 20 mmHg , G3: Stage 2 HTN ≥ 160/100 mmHg , G4:
malignant HTN or hypertensive crisis.

38. Re-challenge or switch to another therapy?
Cetani G et al. Expert Rev Anticancer Ther. 2018;18(8):735-750.
Re-challenge previous regimen
• Previous PFS/free interval:
> 24 months for 1st remission
> 12 months for 2nd remission
> 6 months for subsequent remission
Switch regimen
• Previous PFS/free interval < 24, 12 and 6
months
-Switch bortezomib ↔lenalidomide
combination
-Introduce newer agents
• Progression under therapy or within 60 days
from previous therapy

39. Convenience and Quality of Life
Improvements in QOL, convenience, and burden to health care providers are also of utmost importance

40. Case 2

41. Case 2
• A 70-year-old female patient with standard-risk MM
• Unfit for triplet, started with frontline Rd
• The initial response was good (VGPR), but she progressed on therapy during cycle 26 (after 2
years)
• The salvage therapy consisted of Vd.
• Following the achievement of partial response (PR) after 2 cycles, which was sustained for 3
cycles, the patient progressed again with bone pain, anemia, and an M-spike of >1.5 g/dL.

42. Case 2
• This patient has progressed after both Bortezomib and Lenalidomide therapy
• What will be your next step in management?

43. Relapse/Refractory to Lenalidomide: Pomalidomide-based Regimens
Efficacy
OPTIMISM (N = 559)
PVd vs Vd1
ICARIA (N = 307)
IsaPd vs Pd2
ELOQUENT (N = 117)
EloPd vs Pd3
APOLLO (N=
304)
DPd vs Pd4
PFS HR
(▲mos)
0.61 (▲ 4.1)
11.2* vs 7.1m
0.59 (▲ 5.0)
11.5 vs 6.5m
0.54 (▲ 5.6)
10.3 vs 4.7m
0.63 (▲ 5.5)
12.4 vs 6.9m
ORR, % 82 vs 50 60 vs 35 53 vs 26 51 vs 19.6 ≥ VGPR
• Dara-Kd (CANDOR) in Lena Ref HR 0.457
• Isa-Kd (IKEMA) in Lena Ref HR 0.598
1.Richardson. Lancet Oncol. 2019;20:781. 2. Attal. Lancet. 2019;394:2096. 3. Dimopoulos NEJM. 2018;379:1811. 4. Dimopoulos. ASH 2020. Abstr 412.
5. Otero. EHA 2020. Abstract EP982. 6. Sonneveld. ASH 2018. Abstract 801. 7. Dimopoulos. Lancet. 2020;396:186. 8. Moreau. EHA 2020. Abstr LBA2603.
*17.8 m in Len-Ref 1st
- PomCyDex (n = 100): mPFS 7.6 m (10.4 m in PR)5
- KPomDex (EMN-011; n= 60): mPFS 18 m6

44. Case 2 continue..
• The patient was then treated with pomalidomide-dexamethasone (pom-dex)
• Response to pom-dex lasted for only 5 months before the disease progressed again.
• Following this Daratumumab therapy was started, which induced a PR.
• Last known status: Patient was receiving daratumumab single agent at a dose of
16mg/kg every 4 weeks, with a sustained response, good tolerance, no bone pain, and
normal performance status

45. First Relapse Options
• Any first relapse options that
have not been tried
(2 new drugs;
triplet preferred)
Isa-Pd, or DPd, or DKd, or KPd
• Belantamab mafodotin
• VDT-PACE like anthracycline
containing regimens
• Venetoclax [only t(11;14)]
• Selinexor
• Melflufen
• CAR-T cell therapy
• Bispecific mAbs
• Cyclo / benda / melphalan
• Panobinostat + PI
Additional Options
Myeloma: Second or Higher Relapse
Rajkumar SV © 2020
P. Moreau

46. Second and subsequent relapses

47. Daratumumab Monotherapy in Heavily Pretreated Relapsed/Refractory Myeloma
Response n (%)
ORR (sCR + CR + VGPR + PR)
46 (31)
Best response
sCR
CR
VGPR
PR
MR
3 (2)
4 (3)
13 (9)
26 (18)
9 (6)
≥ VGPR (sCR + CR + VGPR) 20 (14)
≥ CR (sCR + CR) 7 (5)
Pooled analysis of 148 pts treatd with daratumumab
monotherapy in pts who have received ≥2-3 lines of therapy
including iMID and PI or were refractory

48. MAMMOTH: Suboptimal Outcomes in Patients With
MM Refractory to CD38 Antibody
 Retrospective analysis of 275 patients from 14 academic centers
 249 patients received further treatment
‒ ORR: 31%; mPFS: 3.4 mos; mOS: 9.3 mos
Characteristic
Median
OS, Mos
Description
Not triple
refractory
11.2
Refractory to 1 CD38 mAb,
but not to both PI and IMiD
Triple and quad
refractory
9.2
Refractory to 1 CD38 mAb +
1 PI + 1 or 2 IMiDs
Penta
refractory
5.6
Refractory to 1 CD38 mAb +
2 PIs + 2 IMiDs
Overall cohort 8.6
Gandhi. Leukemia. 2019;33:2266.
0 10 50
40
20 30
100
80
60
40
20
0
Mos
Proportion
Surviving
(%)
Not triple refractory (n = 57)
Triple and quad
refractory (n = 148)
Penta refractory (n = 70)
P = .002
OS

49. Surface Antigens on Clonal Plasma Cells
 CD137
 CD56
 CD28
 CD40
 CXCR-4
 PDL1:
‒ durvalumab
 CAR T cell targets:
‒ CD38; daratumumaba, isatuximab, MOR202
‒ SLAMF-7; elotuzumaba
‒ BCMA
‒ CD138
‒ Kappa light chain
Bhatnagar V, et al. Oncologist. 2017;22:1347-53. Gormley NJ, et al. Clin Cancer Res. 2017;23:6759-63.
Jelinek T, et al. Front Immunol. 2018;9:2431. Moreno L, et al. Clin Cancer Res. 2019;epub.
Raab MS, et al. Blood. 2016;128:1152. Rawstron AC, et al. Haematologica. 2008;93:431-8.
aApproved by the FDA and EMA.

50. BCMA-Targeted Therapies
BCMA
Antibody–Drug Conjugates
Belantamab mafodotin
MEDI2228
CC-99712
Bispecific T-Cell Engagers
AMG 420
AMG 701
CC-93269
REGN5458
JNJ-64007957
PF-06863135
Myeloma
cell
CAR T-Cell Therapies
Idecabtagene vicleucel
LCAR-B38M
P-BCMA-101
bb21217
ALLO-715

51. BCMA as a Target in Myeloma Treatment
 BCMA: antigen expressed specifically on PCs and myeloma cells
 Cell-surface receptor in TNF superfamily
 Higher expression on myeloma cells than normal PCs
 Not expressed in other tissues
 Key role in B-cell maturation and differentiation
 Promotes myeloma cell growth, chemotherapy resistance,
immunosuppression in bone marrow microenvironment
 Expression of BCMA increases with progression from MGUS to advanced
myeloma
 Additional ligands for BMCA include APRIL and BAFF
BCMA
Immunoglobulin
BM LN BM, LN
Pro-B Pre-B Transitional Naive GC-B Memory Plasmablast PC
Short-lived PC
Long-lived PC MM
BCMA
BAFF-R
Cho. Front Immunol. 2018;9:1821. Moreaux. Blood. 2004;103:3148. Sanchez. Br J Haematol. 2012;158:727.
BCMA
sBCMA
APRIL
BAFF
γ-secretase
Cell membrane

52. Belantamab Mafodotin (DREAMM-2 Study) in Refractory MM
Lonial. ASCO 2020. Abstr 8536.
Main AEs: Corneal events: 72% to 77%; Thrombocytopenia: 36% to
57%; Infusion-related reaction: 16% to 21%
N = 196 after ≥ 3 prior lines of therapy; refractory or intolerant to IMiDs, PIs, and CD38 antibodies
Median 7 (3-21) prior lines in 2.5 mg/kg cohort and 6 (3-21) in 3.4 mg/kg cohort
• Belantamab mafodotin (GSK2857916): humanized, afucosylated, IgG1 BCMA-targeted ADC that neutralizes soluble BCMA
ORR: 32-35% (by dose)
18% VGPR, 5% CR or sCR at 3.4 mg/kg
≥ MR 40%; ≥ SD 57% at 3.4 mg/kg
Median DOR: 6.2 months 15
OS
Median, Mos
(95% CI)
Bela maf 2.5 mg/kg
(n = 97)
Bela maf 3.4 mg/kg
(n = 99)
OS 14.9 (9.9-NR) 14.0 (10.0-NR)
PFS 2.8 (1.6-3.6) 3.9 (2.0-5.8)
Probability
of
OS
Mos From Randomization
100
80
60
40
20
0
11
0 1 2 3 4 5 6 7 8 9 10 12 16
13 14 17 18
Treatment
2.5 mg/kg
3.4 mg/kg
50% probability
DREAMM-7: Bela Maf + Vd vs DaraVd NCT04246047
DREAMM-5: Bela Maf Combinations NCT04126200
DREAMM-6: Bela Maf + Vd (ORR: 78%) Nooka. ASCO 2020. Abstr 8502.
DREAMM-9: Bela Maf + SoC in ND MM NCT04091126
DREAMM-8: Bela Maf + Pd NCT04484623 29 Pts ( penta Ref)….86% ORR (Trudel. ASH 2020. Abs 725)

53. Selinexor Combination in Relapsed/Refractory MM
1. Chari. NEJM. 2019;381:727. 2. Grosicki. Lancet. 2020;396:1563.
AEs: thrombocytopenia (73%, 58% G3-4), anemia (67%, 44% G3-4),
fatigue (73%; 25% G3-4); GI: nausea (72%, 10% G3/4),
anorexia (56%; 5% G3/4), weight loss (50%; 1% G3/4)
Phase IIb STORM Trial: Selinexor + Dex (N = 122)1
• Exportin 1 (XPO1) is the major nuclear export protein for Tumor suppressor proteins (TSPs, e.g., p53, IkB and FOXO). XPO1 is overexpressed in MM
• Selinexor is an oral selective XPO1 inhibitor
 7 median prior lines of therapy (range: 3-18)
 96% refractory to Btz, Len, carf, pom, dara
PFS
Median PFS: 3.7 mos
Phase III BOSTON Trial: Selinexor + Vd (N = 402)2
 1-3 prior lines of therapy (median: 2; 19% had 3 lines)
 76% exposed to prior PI, 38% prior len
ORR: 26%
≥ MR 39%; ≥ SD 79%
mDOR: 4.4 months
mOS: 8.6 months
HR: 0.70 (P = .0075)
Median PFS, Mos
SVd 13.93
Vd 9.46
ORR: 76% vs 62% (28% VGPR (17% sCR/CR))
mDOR: 20.3 v 12.9 mos
mOS: NR vs 25 mos
PN G ≥ 2: 21% vs 34%, p=0.001
Seli-Pd (STOMP): 52 Pts: 58% ORR; 12m PFS. Chen. ASH 2020. Abs 726.

54. Harrison. ASH 2019. Abstr 142.
PFS in patients with t(11;14)
PFS in all patients PFS by t(11;14) and BCL2 status
PFS
23.2 m (VenBd)
11.4 m (PboBd)
HR: 0.60; P = .001
NR vs 9.3;
HR: 0.09; P = .003 NR vs 9.9;
HR: 0.30; P < .001
VENETOCLAX+ BortDex vs BortDex ( 291 patients, 2:1 random) BELLINI Study
Venetoclax: 800mg QD; BtzDex: C1-8 /21d....C9/35d ....until progression
Venetoclax is a small molecule BCL-2 inhibitor1, induces cell death in MM cell, particularly t(11;14) & high BCL2….0RR: 21%...60%,

55. BCMA CAR T-Cell Studies: Efficacy
Ide-cel (bb2121)
PhII
bb21217 Cilta-cel (JNJ-4528)
Orva-cel (JCAR-
H125)
Cell Dose 150 300 450 150 300 450 0.75 x 106 / kg 300 450 600
Median follow-up,
mos
13.3 17.6 4.0 3.3 11.5 (3.0 – 17.0) 9.5 8.8 2.3
Response Rate
ORR 50% 69% 82% 83% 43% 57% 100% 95% 89% 92%
CR 25% 29% 39% 33% 0% 14% 86% 37% 42% 29%
MRD
Evaluable for
MRD, #
4 70 54 7 6 4 21 11 11 3
MRD- (%) 50% 31% 48% 100%
83.3
%
100% 85.7%
72.7
%
90.9
%
100%
Median DoR, mos NR 9.9 11.3 11.1 NR NR NR NR NR NR
Median PFS 2.8 5.8 12.1 NR NR NR NR 9.3 NR NR
[
Munshi. ASCO 2020. Abstr 8503. Berdeja. ASH 2019. Abstr 927. Berdeja. ASCO 2020. Abstr 8505; Mailankody. ASCO 2020. Abstr 8504.

56. BCMA Bispecific mAb Studies: Efficacy
AMG420 CC-93269 Teclistamab
Dose 400 ug/day 610 mg and 6 mg 270 ug / kg
N 10 9 12
Median follow-up,
mos
NR NR NR
Response Rate
ORR 70% 88.9% 67%
CR 50% 44.4% 25%
MRD
Evaluable for MRD,
#
10 NR 5
MRD- (%) 50% NR 80%
Median DoR, mos 9.0 (range 5.8 –
≥13.6)
11 of 13 ongoing 16 of 21 ongoing
[Many bispecific antibody updates and new presentations at ASH 2020]
Topp. JCO. 2020;38:775. Abstr 8503. Costa. ASH 2019. Abstr 143. Usmani. ASCO 2020. Abstr 100

57. BCMA Therapeutics – Advantages/Disadvantages
Antibody–drug
conjugate
CAR T-cells Bispecific antibody
Off-the-shelf Personalized Off the shelf
Targeted cytotoxicity
Not dependent on T-cell
health
Targeted immuno-cytotoxicity Targeted immuno-cytotoxicity
No lymphodepletion
No steroids
Single infusion
(“one and done”)
No lymphodepletion
Minimal steroids
Available to any infusion
center
Outpatient administration
Potentially persistent
Fact accredited center required
(hospitalization likely required)
Initial hospitalization required
Currently requires
REMS/Ophtho
CRS and Neurotoxicity; requires
ICU and Neurology services
CRS and Neurotoxicity
possible
Single agent activity low in
CD38 refractory patients
Dependent on T-cell health
(manufacturing failures)
Dependent on T-cell health
(T-cell exhaustion)
Requires continuous Requires significant support Requires continuous
Disadvantages
Advantages
$$ $$$$ $$$

58. Myeloma: Future State
Refractory to IMiD, PI, Anti-CD38
Multiple Relapse
Refractory to IMiD, PI, Anti CD38,
Alkylators, and Anti BCMA
Existing drugs:
Elotuzumab
Selinexor
Venetoclax
Panobinostat
Bendamustine
VDT PACE
New Drugs:
New Monoclonals
Iberdomide, CC-94480
New ADCs
New bi-specifics
New CAR-Ts
Combinations with
Cyclophosphamide
that do not have
IMiD, PI, Anti CD38
Anti BCMA strategy
BCMA ADC
(eg., Belantamab)
Bispecific
Anti BCMA
BCMA CAR-Ts
Rajkumar SV © 2020

59. Extramedullary disease (EMD)
Jagosky et al. Curr Hematol Malig Rep. 2020 Apr;15(2):62-71
• Incidence:
• At initial MM diagnosis: 3-5%
• In the relapsed/refractory setting :6-20%
• Median 4yr time span reported between diagnosis and development of EMD
• Male sex and younger age common
• Typically, extramedullary sites involved at diagnosis are the skin and soft tissues with
usually only one site involved
• In relapsed/ refractory disease, sites involved include the kidneys, lymph nodes, central
nervous system (CNS), respiratory tract, gastrointestinal /liver, pleura and pericardium

60. Treatment Considerations
PS-Paraskeletal,BDD- Bortezomib,doxorubicin,dexamethasone, BTD-Bortezomib,Thalidomide,dexamethasone,TD Thalidomide,Dexamethasone
Usmani S et al. Haematologica. 2012; 97(11): 1761–1767.

61. Summary
• Treatment of myeloma has evolved quickly over the past decade, due to:
- Better understanding of disease biology
- New agents with positive clinical trials
- Increasing use of combinations that gives rise to deep responses and better overall outcome
• Goal of first-line therapy is deeper response by using triplet combinations, ASCT for
consolidation, and maintenance
• At relapse, multidrug combinations incorporating new agents obtain maximum benefit
- Patients should be treated to achieve best response while taking into account potential AEs
and maximizing supportive care

62. THANK YOU